Caprin-1 is a target of the deafness genePou4f3and is recruited to stress granules in cochlear hair cells in response to ototoxic damage

Abstract

The POU4 family of transcription factors are required for survival of specific cell types in different sensory systems. Pou4f3 is essential for the survival of auditory sensory hair cells and several mutations in human POU4F3 cause hearing loss. Thus, genes regulated by Pou4f3 are likely to be essential for hair cell survival. We performed a subtractive hybridisation screen in an inner-ear-derived cell line to find genes with differential expression in response to changes in Pou4f3 levels. The screen identified the stress-granule-associated protein Caprin-1 as being downregulated by Pou4f3. We demonstrated that this regulation occurs through the direct interaction of Pou4f3 with binding sites in the Caprin-1 5′ flanking sequence, and describe the expression pattern of Caprin-1 mRNA and protein in the cochlea. Moreover, we found Caprin-1-containing stress granules are induced in cochlear hair cells following aminoglycoside-induced damage. This is the first report of stress granule formation in mammalian hair cells and suggests that the formation of Caprin-1-containing stress granules is a key damage response to a clinically relevant ototoxic agent. Our results have implications for the understanding of aminoglycoside-induced hearing loss and provide further evidence that stress granule formation is a fundamental cellular stress response.

Age-Related Hearing Loss

“…Third, there may be common pathological pathways involved in causing both disorders. Plausible pathways that have been linked to both pathologies include oxidative damage, inflammation, vascular function, mitochondrial dysfunction, glutamate excitotoxicity, and RNA granule dysregulation (Towers et al 2011;Wong and Ryan 2015;Ganguly et al 2017;Maziuk et al 2017;Du et al 2018;Jayakody et al 2018;Ridge and Kauwe 2018). It is also possible that more than one of these models is relevant and that, as well as common causative factors underlying hearing loss and cognitive decline with age, the resulting lack of auditory input accelerates the psychological consequences and hence the clinical impact of the pathology.…”

Cytoplasmic RNA Granules and Viral Infection

“…SGs rapidly form when mammalian cells experience starvation, oxidative or heat stress. However, they also form under certain physiological conditions in cochlear hair cells (73,119) and during types of virus infection (described below). Other physiological roles for RNA granules have been described in translation and development.…”

Bacterial expression and preliminary crystallographic studies of a 149-residue fragment of human Caprin-1

“…Like many RNA-binding proteins (RBPs) found in SGs, Caprin-1 promotes SGs when it is overexpressed. In cochlear hair cells, CAPRIN1 transcription is down-regulated by the transcription factor Pou4f3 (Towers et al, 2011), which is essential for the survival of auditory sensory hair cells (Xiang et al, 1997). Several mutations in the human Pou4f3 gene cause hearing loss Pauw et al, 2008).…”